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Protein kinase C iota (PKCι) is overexpressed in non-small-cell lung cancer, ovarian, and pancreatic cancers, where it plays a critical role in oncogenesis. The gold compound aurothiomalate (ATM) has been shown to inhibit PKCι signaling and exerts potent antitumor activity in preclinical models. We sought to determine the maximum tolerated dose (MTD) of ATM. We conducted a phase I dose escalation trial of ATM in patients with non-small-cell lung cancer, ovarian or pancreatic cancer. Patients received ATM intramuscularly weekly for three cycles (cycle duration 4 weeks) at 25, 50, or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Blood samples were analyzed for elemental gold levels. Patients were evaluated every 4 weeks for toxicity and every 8 weeks for response. Fifteen patients were enrolled in this study. Six patients were treated at 25 mg, seven at 50 mg, and two at 75 mg. There was one dose-limiting toxicity at 25 mg (hypokalemia), one at 50 mg (urinary tract infection), and none at 75 mg. There were three grade 3 hematologic toxicities. The recommended MTD of ATM is 50 mg. Patients received treatment for a median of two cycles (range 1-3). There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold consistent with linear pharmacokinetics. In summary, this phase I study was successful in identifying ATM 50 mg intramuscularly weekly as the MTD. Future clinical investigations targeting PKCι are currently in progress.

Gold levels in the plasma and blood cells of patients treated with the gold drug Myocrisin (sodium aurothiomalate) were determined by atomic absorption spectrometry. There is a correlation between whole blood gold and plasma gold concentrations which is different for smokers and non-smokers. Most cellular gold is associated with the membrane and is present in concentrations approximately equivalent to the number of reactive sulphydryl groups on the exofacial surface of the cell. Since gold would be expected to react with SH groups and since these groups are vital for cellular function, a possible role for gold in modifying cellular metabolism is indicated.

In order to study the effect of gold compounds on the action of thrombin in vivo, experiments were performed to measure platelet survival and the weight of thrombus formation in experimental models of intra-aortic thrombosis by two indwelling aortic catheter methods. We have called these the long and short catheter methods. Platelet survival was reduced in all gold-treated and control animals which had indwelling aortic catheters. In the long catheter model, New Zealand White male rabbits were treated with one of the following: gold sodium thiomalate, sterile water, gold thioglucose, gold sodium thiosulfate, disodium thiomalate. Gold sodium thiomalate-treated rabbits had a reduced weight of experimentally induced intra-aortic thrombi compared with animals treated with sterile water or equimolar concentrations of gold thioglucose, gold sodium thiosulfate, or disodium thiomalate. This reduction in thrombus weight in the animals treated with gold sodium thiomalate was not reflected by changes in platelet survival or fibrinolysis. The serum gold levels achieved in these in vivo experiments was in the range of 5.0 X 10(-5) to 1.0 X 10(-4) M. These values are comparable to levels which can be achieved in human subjects immediately after a gold injection. In the short catheter model, New Zealand White male rabbits were treated with either gold sodium thiomalate, gold thioglucose, disodium thiomalate, or auranofin. Controls were given either water or 0.05% chlorocresol. Water-treated and gold sodium thiomalate-treated animals were also given 51Cr-labeled platelets and 125I-fibrinogen before insertion of the catheter.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: One hundred twenty-one patients with active RA were randomly assigned to receive 6 mg auranofin (AF)/day (60 patients) or 50 mg gold sodium thiomalate (GST)/week (62 patients) in a double-blind fashion. There were no intergroup differences with respect to sex, age, duration (median 2 years), stage and activity of the disease. In the case of "striking improvement" after 24 weeks a dose reduction to 50 mg GST/month or 4 mg AF/day was allowed and carried out in all GST patients and no AF patient. The serum gold levels were 5 times higher with weekly GST, they approached those of the AF group with monthly GST injections. The clinical parameters--number of swollen joints, activity index, articular index, grip strength, ESR--improved significantly in both groups, but grip strength, articular index and ESR improved more pronounced in the GST group. The X-ray progression (hands and forefeet) was significantly greater in the AF group. Forty-eight AF patients (80%) and 39 GST patients (36%) completed the first year. Thereafter the study was continued as an open study but the patients were allowed to switch from GST to AF. After the first and second year 14/7 GST patients switched to AF. The second/third year was completed by 37/22 AF pat. (62%/37%) and by 15/8 GST pat. (24%/13%). Skin reactions were more common with GST (41.9%/26.7%), diarrhoea was more common with AF (36.7%/19.4%), proteinuria occurred in 10% in both groups, leucopenia and thrombocytopenia were rare in both groups (1.7%). The withdrawal rate due to adverse events was 10%/26% in the AF/GST group during the first year (p less than 0.05) and 25%/32% over the three year period (n.s.)., Conclusion: Both AF and GST are effective in the long-term treatment of RA, but GST is more so in radiological progression and ESR.

The report concerns a mother who breast fed her infant whilst receiving sodium aurothiomalate for the treatment of rheumatoid arthritis. The milk:serum concentration ratio was not constant, reflecting the non-concurrence of the concentration-time profiles of gold in milk and maternal serum after i.m. injection. Gold was detected in the infant's serum. Calculations indicate that the weight-adjusted dose to the infant exceeded that received by the mother.

Plasma and erythrocyte gold concentrations were measured in 35 patients taking gold sodium thiomalate (GSTM) for rheumatoid arthritis. In 6 patients with adverse effects attributable to gold therapy at the time of sampling, gold concentrations in plasma and erythrocyte fractions were no different from those without adverse effects. A significant difference was seen in the distribution of gold in the blood of cigarette smokers compared to non-smokers, with smokers having higher erythrocyte and lower plasma gold concentrations. A prospective study on 15 patients commencing treatment with GSTM showed that the higher concentrations of erythrocyte gold seen in smokers were achieved within the first 2 weeks of treatment.

Comparison of maintenance injections of sodium aurothiomalate given at two-week or four-week intervals revealed no significant clinical or radiological differences over a six-month period. Higher serum gold levels were achieved with the more frequent injections and these were associated with a more pronounced fall of ESR during maintenance therapy. Whether this has any special implications for the subsequent progress of patients treated by the two regimes remains to be determined.

A prospective controlled, double-blind multicenter trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombocytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, "nitritoid" reactions, and "gold pneumonitis" were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.

The mitogenic response of peripheral blood lymphocytes from 21 patients with rheumatoid arthritis to concanavalin-A (con--A), phytohaemagglutinin (PHA), and pokeweed mitogen (PWM) was significantly lower than in 30 normal subjects. After 15--24 weeks' treatment with sodium aurothiomalate (GST) the response to these mitogens rose to within the normal range. Improvement over pretreatment values was significant for con-A and PWM measured as area under the dose response curve but only for con--A if response at optimal mitogen concentration is the sole criterion. The improvement in PHA response was not significant with either method of measurement. There was an improvement in disease activity by 15--24 weeks as measured by a fall in serum C-reactive protein (CRP), IgM rheumatoid factor (RF), Clq binding activity (ClqBA), and Ritchie articular index. Con--A lymphocyte responsiveness was inversely related to serum CRP levels, but measurements of disease activity were otherwise unrelated to lymphocyte mitogen responsiveness. The observed improvement in peripheral blood lymphocyte responsiveness during gold treatment contrasts with the suppressive effect of gold in vitro. We suggest that the improvement in lymphocyte function is due to the lessening of rheumatoid disease activity during gold treatment, and that the low serum gold levels in our patients were insufficient to mask this effect. Sera from some of our patients were capable of suppressing the function of normal lymphocytes, and this was less apparent after treatment. The suppressive effect of sera correlated with ClqBA. Suppressive factors in serum, including possibly immune complexes, may be one factor leading to suppression of lymphocyte function during rheumatoid arthritis. Such an inverse relationship between humoral and cellular immune mechanisms might influence the clinical expression of rheumatoid arthritis.

The activity of gold sodium thiomalate (GST) given i.m. to adjuvant-induced polyarthritic rats was studied alone or in combination with active doses of aspirin, indomethacin and hydrocortisone. In addition to paw volume and body weight changes, erythrocyte sedimentation rate, serum albumin/globulin and gold levels as well as plasma activities of beta-glucuronidase, acid phosphatase, lysozyme and lactic acid dehydrogenase were measured. In prophylactic studies the beneficial activity of GST was unaffected by aspirin, suggesting a positive drug interaction, but additive with indomethacin or hydrocortisone for the 1st but not 2nd lesion of the disease. These results were closely correlated with increased serum gold levels. Similar clinical findings were observed in therapeutic studies except that a positive drug interaction occurred between GST and hydrocortisone. Unlike in the prophylactic experiments, serum gold levels were unaffected by any of the agents tested in the therapeutic studies.

As used clinically, Myocrisin appears to contain largely polymeric (Autm)n, in which thiomalate (tm) sulphurs bridge between Au(I) ions, together with small amounts of a more reactive gold-bound thiomalate, and free thiomalate, as well as glycerol, unidentified yellow-products from autoclaving and phenylmercury adducts. Solganal usually contains thioglucose sulphinic acid as an impurity. Auranofin, on the other hand, has been crystallised. It is monomeric and Au(I) is almost linearly coordinated by P and S from triethylphosphine and tetraacetyl-beta-D-thioglucose, the latter adopting the chair conformation in the solid state and in solution. The major reaction of auranofin in acidic aqueous solutions appears to be hydrolysis of the sugar acetyl groups but other products arise if methanol is also present in the medium. NMR methods are used to examine in vitro the partition of auranofin between plasma and blood cells. The displacement of the thioglucose ligand and release of PEt3 from gold as OPEt3 are discussed.

Serum, blood and cell-associated gold were determined at various time periods after intravenous administration of 1 mg Au/kg of auranofin (AF), gold sodium thiomalate (GSTM) and aurothioglucose (GTG). AF gold exhibited an early phase of decay with high levels of cell-association; whereas, after 72 h cell-associated gold was not detectable. In contrast, GSTM and GTG serum gold values were generally higher than blood values since cell-associated gold rarely occurred. These observations suggest that, in contrast to GSTM and GTG, intravenous administration of AF results in a dynamic equilibrium of gold between the cellular and serum compartments of blood.

Three techniques of gold analysis, flame and electrothermal atomic absorption spectrometry and neutron activation analysis, have been compared, using plasma and plasma fractions (derived by gel chromatography) from rheumatoid patients receiving aurothiomalate therapy and from plasma samples incubated with aurothiomalate in vitro. The three methods correlated well in the analysis of gold in whole plasma, but only neutron activation analysis was suitable for the assay of all the plasma fractions. The susceptibility of the two atomic absorption methods to interference by sodium chloride was investigated.

We evaluated the antiarthritic activity of gold sodium aurothiomalate (GSTM) and auranofin (AF) against experimental polyarthritis induced in 3 rat strains using 3 different adjuvants. These 2 gold drugs were found to either stimulate, inhibit or have no effect upon the development of arthritis, dependent upon the rat strain and/or the adjuvant used. The ambivalent antiarthritic activities of GSTM and AF did not appear to be associated with any variations in serum gold levels. These results highlight the need for caution in studying gold drugs using the adjuvant polyarthritic model in the rat and, if used, the need to define clearly the strain/adjuvant/gold drug combination. Within these constraints however, our findings support the concept that GSTM and AF have different mechanisms of action.

A multicenter double-blind comparative study with auranofin (Ridaura) and Na-auro-thiomalate (Tauredon) was carried out in order to investigate under controlled conditions whether the new oral gold compound may be an alternative to injections of gold salts. 121 patients were included in the study, data of 86 patients treated for at least one year could be analysed. The following parameters were examined at regular intervals: number of painful and swollen joints, grip strength, morning stiffness, pain and general health on the visual analogue scale, ESR; from these data the articular index and activity index (according to Lansbury, with slight modifications) were calculated. Blood samples for routine safety monitoring and serum gold levels as well as urine tests were obtained regularly. Both treatment groups showed similar improvement in the values for efficacy measurements after one year, starting within 8 to 12 weeks. Patients in the auranofin group with a disease duration of less than 2 years showed greater improvement in the values for efficacy assessment with the exception of grip strength and the number of tender joints than patients with a disease duration of 2 years or more. No such trend was seen in the Tauredon-subgroups. Numerous side effects were recorded in both groups: 89.7% of the patients on Tauredon and 68.8% of the patients on auranofin had observed one symptom during the course of one year. There was a clear distinction concerning the nature of side effects: mucocutaneous symptoms, especially rash and pruritus, were approximately twice as common with Tauredon, whereas diarrhoea was much more frequent in patients treated with auranofin.(ABSTRACT TRUNCATED AT 250 WORDS)

We assessed the effects of administration of gold sodium thiomalate on the clinical and immunologic manifestations of type II collagen-induced arthritis in rats. Injections of varying doses of gold did not alter these parameters significantly. Thus, there was no evidence in this animal model that gold possesses either antiinflammatory or immunosuppressive properties.

Sixty-three patients with rheumatoid arthritis were randomly divided into 3 groups, and treated with either sodium aurothiomalate (Myocrisin), auranofin, or placebo. Gold levels in whole blood, plasma, and haemolysate were measured serially along with clinical and laboratory parameters of efficacy. Auranofin produced a higher ratio of haemolysate to plasma gold than Myocrisin, and it appears that the affinity of the red cell for gold is reduced during therapy with auranofin. Gold levels did not correlate with changes in the pain score, erythrocyte sedimentation rate, and C-reactive protein, nor with the development of toxicity. In the Myocrisin group the haemolysate gold level achieved was dependent on the number of cigarettes smoked. In the auranofin group there was no such correlation, but the haemolysate gold level was higher for smokers than non-smokers. The likely action of gold is discussed.

The distribution of gold among the globulin, albumin, and unbound fractions of plasma, obtained either from rheumatoid patients receiving long-term aurothiomalate therapy or from samples incubated with aurothiomalate in vitro, has been investigated. In the rheumatoid patients it has been found that, although the majority of the plasma gold is always bound to albumin, the distribution varies cyclically in phase with the dose schedule. An explanation of these phenomena is provided, based on data obtained from the reaction between aurothiomalate and plasma constituents in vitro.

Measurements have been made using electrophoresis and neutron activation analysis of the distribution of gold in the blood of four patients who have responded well to chrysotherapy for rheumatoid arthritis. It has been shown that in these patients there is litte, if any, binding to the fibrinogen. The majority of protein-bound gold is associated with the albumin but significant amounts are bound to the other proteins. There is a small amount of gold associated with the blood cells.

Serum from patients with rheumatoid arthritis (RA) receiving disodium aurothiomalate was analysed for total gold by atomic absorption spectrometry and for unbound (free) gold by the same method after ultrafiltration by an inert membrane. It was shown that it is possible to obtain reliable free gold concentrations by this method. Good correlations were shown between total and 'free' gold and between total and protein bound gold (PBG) for 54 patients with RA who were stabilised on gold therapy. Significant correlation was also shown between the same parameters for a second group of 15 patients starting gold therapy who were bled at weekly intervals for nine weeks immediately before medication. A single correlation with regression for all patients studied again showed good correlation between total and free gold and between total and PBG. Of the 189 paired values plotted, 182 fell within 2SD of the regression lines for the two plots. Of the seven patients with results outside 2SD of the regression line, six presented with side effects during the study.

Serum levels after oral administration of 30 mg/kg of sodium aurothiomalate (Myocrisin), triethylphosphine gold chloride, or triphenylphosphine gold chloride to guinea pigs indicated that all were orally absorbed. However, the serum gold level of triethylphosphine gold chloride was three to four times that of Myocrisin or triphenylphosphine gold chloride and was comparable with the serum level produced when the same dose of Myocrisin was injected intramuscularly. A comparative time-course study between intramuscular administration of Myocrisin and oral administration of triethylphosphine gold chl;ride indicated that during the first 24 hours after intramuscular injection of Myocrisin, a large fraction of the gold was not protein-bound, whereas all detectable gold in serum after oral administration of triethylphosphine gold chloride was protein-bound. Gold levels in the separated protein fractions indicate that the gamma-globulin level after oral administration of triethylphosphine gold chloride is approximately three times higher after 24 hours than with intramuscular Myocrisin.

On-line separation and detection of both high- and low-molecular-weight gold species in human blood plasma treated with disodium aurothiomalate were achieved by a technique incorporating a combination of fast protein liquid chromatography with continuous monitoring of absorbance at 254 nm and eluant gold concentration by flame atomic absorption spectroscopy. The fate of gold (40 microM disodium aurothiomalate) in human blood plasma was monitored over a period of 24 h. Results obtained indicated that more than 50% of the gold is associated with a peak identified as albumin after a 5 min incubation period at 37 degrees C, and by 30 min more than 90% is found to be associated with albumin. This novel analytical combination enables the rapid, selective and sensitive determination of gold(I) and its biotransformation products (both protein--and non-protein-bound) in biological fluids.

Sodium aurothiomalate (ATM), gold keratinate and five different tetracyclines were investigated for activity against M. arthritidis strain ATCC 14124 and M. pulmonis strain JB, both in vitro and in rodents with arthritis caused by these mycoplasmas. In vitro, ATM had only slight activity against M. arthritidis and M. pulmonis, while gold keratinate was virtually inactive against M. pulmonis. In contrast, the tetracyclines were highly active against both mycoplasmas. The tetracyclines and the gold salts were both predominantly mycoplasmastatic. In both rats and mice, parenteral administration of ATM, begun shortly before or after infection of rodents with mycoplasmas, prevented the development of arthritis. ATM or gold keratinate, given subcutaneously to mice already arthritic from infection with M. pulmonis, reduced the severity of the arthritis, even although gold keratinate was inactive aganist this mycoplasma in vitro. Moreover, direct testing of serum, collected from mice treated with gold keratinate, failed to demonstrate antimycoplasmal activity in vitro. These results suggest that the action of gold-containing drugs in mycoplasmal arthritis is due to biological properties of gold other than antimycoplasmal activity. Tetracyclines were also found to be effective in preventing arthritis in rats and mice when given subcutaneously. With high doses, subcutaneous, but not oral, therapy significantly reduced the severity of established arthritis in mice infected with M. pulmonis. The blood levels achieved with the different tetracyclines, when related to their therapeutic activity, indicated that good antimycoplasmal activity and adequate absorption from the gut were not the only properties needed for optimal effectiveness. The results are discussed in relation to treatment of rheumatoid patients with tetracycline HCl.

The uptake of gold by the red blood cells (RBC) of patients treated with aurothiomalate (GSTM) was greatly potentiated by smoking. The ratios of gold concentrations in RBC to the concentrations in plasma were 0.35 +/- 0.07 (mean +/- SE, n = 14) in smokers and 0.028 +/- 0.003 (n = 23) in non-smokers. Gold uptake by RBC in vitro was also greater in smokers than in blood from non-smokers. Thiocyanate appears to be a major factor which enhances the uptake of gold by RBC. The toxicity of GSTM was not altered by smoking but side effects occurred earlier in smokers.

Two normal males participated in a study designed to examine the disposition of gold given intravenously and intramuscularly as gold sodium thiomalate. Blood samples were collected for 30 days, urine and feces for ten. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 12.5 days. Absolute bioavailability of IM gold sodium thiomalate appears to be variable with one subject having complete absorption and the other absorbing 64% of the administered IM dose. The major route of elimination of an IV dose of gold sodium thiomalate is urinary excretion, with a mean of 35% of the dose found in the urine in ten days. Fecal elimination accounts for an additional 9.4% of the IV dose excreted in ten days, probably as a result of biliary secretion.

We investigated the correlation between whole blood gold concentrations and clinical outcomes in 59 auranofin-treated patients and 51 gold sodium thiomalate-treated patients who completed a 21-week, placebo-controlled, multicenter parallel trial. Whole blood gold concentrations did not correlate with clinical outcome, as assessed by changes in joint tenderness, joint swelling, or Westergren erythrocyte sedimentation rate. They also did not correlate with toxic reactions necessitating withdrawal from the study.

A double-blind clinical trial on 60 patients with rheumatoid disease comparing 10 mg sodium aurothiomalate weekly to 50 mg weekly is continuing. An initial report on thirty of these patients, who had completed a year of treatment, shows no statistically significant difference in the response between the two groups. No conclusions can be drawn about toxic reactions in this number of patients having received treatment for only one year.